Jonathan A. Oler HHS Public Access Andrew S. Fox Steven E ...

Amygdalar and hippocampal substrates of anxious temperament differ in their heritability

Jonathan A. Oler1,3,*, Andrew S. Fox2,4,*, Steven E. Shelton1,3, Jeffrey Rogers5,6, Thomas D. Dyer6, Richard J. Davidson1,2,3,4, Wendy Shelledy6, Terrence R. Oakes4, John Blangero6, and Ned H. Kalin1,2,3,4

1Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin, USA

2Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin, USA

3HealthEmotions Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, USA

4Waisman Laboratory for Brain Imaging and Behavior at the University of Wisconsin-Madison, Madison, Wisconsin, USA

5Baylor College of Medicine, Houston, Texas, USA

6Southwest Foundation for Biomedical Research, San Antonio, Texas, USA

Abstract

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident

early in life that is characterized by increased behavioural and physiological reactivity to mildly

threatening stimuli 1–4. Studies in children demonstrate that AT is an important risk factor for the

later development of anxiety disorders, depression, and comorbid substance abuse 5. Despite its

importance as an early predictor of psychopathology, little is known about the factors that

predispose vulnerable children to develop AT and the brain systems that underlie its expression.

To characterize the neural circuitry associated with AT and the extent to which the function of this

circuit is heritable, we performed a study in a large sample of rhesus monkeys phenotyped for AT.

Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously

assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological

condition that elicits the phenotype. High-resolution 18F-deoxyglucose positron emission

tomography (FDG-PET) was selected as the imaging modality since it provides semi-quantitative

indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and

brain activity, and has a time course suited to assess temperament-associated sustained brain

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

Correspondence and requests for materials should be addressed to N.H.K ([email protected]).*These authors contributed equally to this work.

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

Author Contributions N.H.K., S.E.S., J.R. and A.S.F. designed the study. S.E.S oversaw data collection. J.A.O., A.S.F., and N.H.K. analyzed the imaging data. T.R.O., A.S.F. and J.B. developed analytical tools. R.J.D. provided theoretical assistance. J.R. and W.S. performed the genotyping and maintained the pedigree record. J.R., W.S., T.D.D. and J.B. performed the genetic analyses. J.A.O., N.H.K., A.S.F., J.R. J.B. and R.J.D wrote the paper.

Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

HHS Public AccessAuthor manuscriptNature. Author manuscript; available in PMC 2011 February 01.

Published in final edited form as:Nature. 2010 August 12; 466(7308): 864–868. doi:10.1038/nature09282.

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

http://www.nature.com/nature

http://www.nature.com/reprints

responses. Results demonstrated that the central nucleus region of amygdala and the anterior

hippocampus are key components of the neural circuit predictive of AT. Quantitative genetic

analysis demonstrated significant heritability of the AT phenotype. Additionally, a voxelwise

analysis revealed significant heritability of metabolic activity in AT-associated hippocampal

regions. However, activity in the amygdala region predictive of AT was not significantly heritable.

Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differed

from each other. Even though these structures are closely linked, the results suggest differential

influences of genes and environment on how these brain regions mediate AT and the ongoing risk

to develop anxiety and depression.

Anxiety disorders are among the most common forms of psychopathology 6, and frequently

begin during childhood and adolescence. While all children experience acute anxiety,

children with AT display extreme behavioural and physiological reactivity to novel stimuli

and in the presence of strangers inhibit their locomotor activity and vocalizations 3.

Furthermore, children with AT are maladaptively shy and chronically suffer from worry and

apprehension. Some children with AT also exhibit increased pituitary-adrenal and

autonomic activity 4. Identifying neural intermediate phenotypes of AT is a critical step in

elaborating how environmental and genetic factors influence the development of anxiety and

affect-related psychopathology. While AT is assumed to be partially heritable, the extent to

which genetic variation influences metabolic activity in the neural circuit that underlies AT

remains to be determined. We previously validated a nonhuman primate model of AT 7 and

demonstrated that brain activity assessed across stressful and non-stressful contexts

predicted AT, revealing the stable trait-like characteristics of brain metabolic activity

associated with this disposition 2.

To characterize the extent to which individual differences in AT-related brain activity are

heritable, we concomitantly assessed AT and regional brain metabolism in 238 young rhesus

monkeys (male = 116, female = 122, mean age = 2.4 years, range = 0.74 – 4.2 years)

belonging to a multigenerational single-family pedigree of more than 1500 individuals. The

statistical power of an extended pedigree approach to quantitative genetic analysis is derived

from the presence of substantial numbers of closely related, more distantly related, and

unrelated pairs that all contribute information concerning the effects of kinship (shared

genes) on phenotypic similarity (see supplementary information).

Similar to AT in children, monkey AT was assessed using measures of threat-induced

freezing behaviour and inhibited vocalizations, as well as plasma cortisol concentrations

(see supplementary information). AT and brain metabolism were assessed when monkeys

freely behaved in a test cage by themselves for 30 minutes in a potentially threatening

situation in which a human “intruder” entered the room and stood 2.5 meters from the cage

8. During this time the intruder presented his profile to the monkey ensuring that he avoided

eye contact with the animal (No Eye Contact; NEC). Animals with the greatest AT froze

longer, vocalized less, and had elevated plasma cortisol levels. The rationale underlying the

use of the NEC paradigm is: 1) it optimally elicits the behaviours associated with the AT

phenotype 8, 2) increased amygdala metabolism occurs during NEC 2, and 3) selective

dorsal amygdala lesions attenuate NEC-induced behavioural and physiological responses 9.

Oler et al.

Nature. Author manuscript; available in PMC 2011 February 01.

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

To further understand the relation between regional brain activity and AT, monkeys were

injected with FDG immediately prior to NEC. Following NEC exposure, blood was

collected for cortisol assessment and monkeys were anesthetized and placed in a high-

resolution microPET scanner to measure the FDG uptake that occurred during the NEC

challenge. FDG is glucose analog with a half-life of 110 minutes that is trapped by

metabolically active cells. Since the time course of FDG uptake reflects brain activity over

an approximate 30-minute period, and remains stably detectable in the brain, it is an ideal

radiotracer to simultaneously study behaviour and brain activity elicited by exposure to

ethologically relevant situations. Furthermore, FDG-PET allows for measurement of brain

activity within a single condition, and unlike fMRI does not require a contrast with a

baseline signal. These features make FDG-PET particularly useful in understanding the

sustained brain responses associated with temperament, which by definition is a persistent

and relatively context-independent disposition.

The results demonstrated highly significant correlations between individual differences in

AT and glucose metabolism within several large clusters (left and right anterior temporal

lobe, midline parietal cortex, left and right visual cortex, right posterior thalamus and right

temporal parietooccipital area; see Table 1). The anterior temporal lobe clusters (Fig 1) are

of particular interest since they contain the amygdala, extended amygdala and anterior

hippocampus, regions consistently implicated in mediating emotional behaviour, fear-related

responses, and anxiety and depressive disorders 1,10–14. Mean glucose metabolism in the

left and right anterior temporal lobe clusters (residualized for age, sex and mean gray matter

probability) accounted for 24.4% and 27.5% of the variance in AT, respectively. Because

these clusters contain anatomically distinct brain structures, we sought to specify the regions

within the anterior temporal lobe clusters that most strongly predicted AT (i.e., the global

maxima of the right and left clusters). The voxels most strongly predictive of AT were

located in the lateral portion of the right dorsal amygdala (r=0.44, p=2.38e-13; Fig 1A and

Fig 2A), which contains the central nucleus of the amygdala (CeA) and the amygdalostriatal

transition zone (ASTZ), and in the left hippocampus (r=0.45, p=8.3e-13; Fig 1E and Fig

2B). No effects of sex or laterality were observed in any of the reported correlations (all p’s

> 0.10), nor were there any significant main effects of sex on the components of AT (all p >

0.10).

The amygdala and hippocampus work in concert in mediating emotion-modulated memory

15, however, it is important to emphasize that these structures uniquely contribute to other

aspects of emotional processing. For example, hippocampal lesions in rats and rhesus

monkeys produce alterations in anxious behavior that are distinct from the effects of

amygdala lesions 16–18. As the dorsal amygdala and anterior hippocampus are adjacent

structures, calculating the spatial confidence intervals around the voxels containing the

maximum t-values further delineated the locations of these peaks. The confidence intervals

represent volumes that with 95% certainty contain the peak correlations between metabolic

activity and AT (see supplementary information). To further demarcate the location of these

peaks the volumes contained within these confidence intervals were superimposed on a

voxelwise map of [11C- DASB] serotonin transporter (5-HTT) binding created from an

independent sample of rhesus monkeys (see supplementary information). This 5-HTT map,

thresholded at 250× background binding, can be used to precisely localize the CeA and

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

differentiate it from the anterior hippocampus, since compared to surrounding regions the

lateral division of the CeA has the highest density of 5-HTT binding 19. As can be seen in

Fig. 1A–D, the right dorsal amygdala 95% confidence interval encompasses the lateral

region of the right CeA and the laterally adjacent ASTZ. Anatomical studies show that the

ASTZ shares many similarities with the CeA, and may represent a posterior division of the

ventral striatum/extended amygdala 13. The left hippocampal 95% confidence interval does

not overlap with the lateral CeA region as defined by 5-HTT binding, further confirming the

spatial dissociation between the dorsal amygdala and anterior hippocampal regions

predictive of AT (Fig 1E–H).

To estimate the heritability of AT, the pedigree relationships and individual phenotype

measures were used in maximum likelihood variance components analyses computed using

SOLAR (see supplementary information). Consistent with prior findings in rhesus monkeys

20, as well as studies of human anxiety 21, AT was significantly heritable (h2=0.36,

p=0.015). A voxelwise heritability analysis for brain activity was performed using SOLAR

controlling for the potential confounds of age, age2 and sex. Analyses were limited to those

voxels within the FDG clusters that were significantly predictive of AT. Since previous

studies demonstrated that heritable individual differences in brain structure relate to stress

reactivity 22, gray matter probability was also included as a voxelwise covariate. Glucose

metabolic activity was significantly heritable in voxels in the anterior temporal lobe clusters

(Fig 3) as well as in the other clusters predictive of AT (see supplementary information).

Within the anterior temporal lobe clusters, significantly heritable regions were found in

bilateral hippocampus (right sided maximally significant heritable voxel: h2=0.65,

p=3.83e-05; left sided maximally significant heritable voxel: h2=0.76, p=3.4e-06) and in the

right superior temporal sulcus (maximally significant heritable voxel: h2=0.46, p=5.92e-03).

No significantly heritable voxels were observed in the amygdala regions predictive of AT

(see Fig 3). As with any null finding, the possibility exists that significant heritability of

amygdala metabolic activity could be detected with a larger sample.

The heritability estimates for the peak AT-predictive hippocampal and amygdala voxels

were: h2=0.52 (p=0.001) and h2=0.02 (p=0.454), respectively. To test whether the

heritability of metabolic activity in these hippocampal and amygdala AT-predictive voxels

significantly differed from each other, a model that allowed the two heritability estimates of

these voxels to vary independently was compared with a model that constrained the

heritability estimates to be equal. The observed difference in heritability between the

hippocampal and amygdala peak voxels was 0.518 (95% CI: 0.238 – 0.799). Results

confirmed that the heritability of metabolic activity in the anterior hippocampal voxel was

significantly greater than that in the dorsal amygdala voxel (χ2=6.08, df=1, p<0.0137). A

similar difference in heritability was found for the amygdala and hippocampal regions

defined by the 95% spatial confidence intervals of the most AT-predictive peaks (χ2=6.24,

df=1, p<0.0125). For these regions the observed difference in heritability was 0.508 (95%

CI: 0.218 – 0.798). These results suggest that the heritable risk to develop AT is more likely

to be related to hippocampal, and not amygdala, metabolic activity when assessed during the

NEC condition. Given that the amygdala and anterior hippocampus are anatomically linked,

and are both highly predictive of AT, we did not expect the heritability of these regions to be

dissociable. Demonstrating differential heritability between these two closely related

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

structures is highly valuable as it provides new insight into the neural circuits underlying

AT. Additionally, it establishes a model system that can be used to further investigate the

genetic and environmental mechanisms that may differentially affect amygdala and

hippocampal function relevant to the development of anxiety-related psychopathology.

Since heritability estimates are influenced by context, environmental variation, and

population characteristics including age 23,24, it is possible that greater heritability of

amygdala function would be detected when examining different phenotypes, other

developmental stages, or when using different paradigms to understand other amygdala-

dependent functions.

The lack of significant additive genetic effects (heritability) observed in the amygdala region

may appear to be inconsistent with the numerous reported effects of single genes, most

notably the repeat length polymorphism in the promoter region of the serotonin transporter

gene (5HTTLPR), on emotion-related amygdala reactivity 25–28. The majority of these

single gene effects are context-dependent, revealed by comparing acute changes in

amygdala reactivity to a baseline state. In a previous study, with a considerably smaller

sample of monkeys, we demonstrated such context-dependent effects of the 5HTTLPR on

amygdala metabolic activity by comparing an activated state to a baseline condition 29. To

further understand similarities between the current paradigm and those demonstrating

influences of single genes on amygdala reactivity, animals were genotyped for the

5HTTLPR and measured genotype analyses, sensitive to effects of single genes, were

performed. Results demonstrated no significant effect of the 5HTTLPR on either AT (p =

0.271) or metabolism in the amygdala and hippocampal regions predictive of AT (FDR q >

0.05). These data are consistent with a recent large-sample human study that failed to

demonstrate a relation between the 5HTTLPR and resting amygdala activity as measured

with perfusion MRI, which like FDG-PET does not require a comparison condition 30.

These findings emphasize the importance of distinguishing between studies assessing

sustained trait-like brain responses associated with AT from those investigating acute

reactivity of the amygdala in relation to adult anxiety.

While the amygdala and hippocampus have been recognized as important in emotion and

psychopathology, little data exist regarding the role of these regions in the development of

temperamental dispositions such as AT. Recent theories have implicated the amygdala in

mediating acute fear and vigilance 11,12, whereas the hippocampus has primarily been

linked to mechanisms underlying declarative memory 15. Of interest, earlier theorists

emphasized the septo-hippocampal system as being central to anxiety and specifically

involved in threat-related behavioural inhibition 10. The current findings provide support for

an important role of the anterior hippocampus in the development of anxious dispositions

16,17, and suggest that the highly interconnected regions of the hippocampus and amygdala

are differentially influenced by genetic and environmental factors. These data support a new

model combining measures of metabolic brain activity with ethologically relevant

behavioural challenges to discover genes that mediate the endophenotype underlying the risk

to develop anxiety and depression.

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

METHODS SUMMARY

Functional and structural (MRI) brain data for each animal were co-registered to a standard

space based on an age-appropriate rhesus monkey brain template. Whole-brain linear

regression analyses examined the relations between FDG uptake and AT. To account for

potential confounds, age and sex were included in the regression model as covariates. Gray

matter probability was also included as a voxelwise covariate to account for the possibility

that structural differences affected the relation between brain metabolic activity and AT. The

resulting 3D t-map was corrected for multiple comparisons using the Šidák equation (1 − (1

− α)1 / n), which is similar to the Bonferroni method and determined the statistical threshold

of p=0.05, corrected (t > 5.47). To estimate the heritability of AT, phenotypic covariance/

correlation amongst pairs of relatives was modeled as a function of expected pairwise

kinship values to estimate the magnitude of additive genetic variance relative to that of the

observed phenotypic variance. Age, age2 and sex were included in the mean effects model

as covariates to control for these potential confounds. The resulting heritability data were

corrected for multiple comparisons based on the total volume of all the clusters correlated

with AT using a False Discovery Rate (FDR; q-value = 0.05). Measured genotype analyses

use the same variance components approach as the heritability analyses, and were

implemented using SOLAR. Measured genotype analyses simultaneously estimate the effect

of specific genotypic differences among animals and the overall effect of pair-wise kinship,

thus testing for the effect of a single polymorphism while accounting for background allele

sharing across the genome due to genealogical relatedness. Full details on methods and any

associated references are presented in the Supplemental Information.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

Acknowledgements

This work has been supported by NIH grants MH046729 (N.H.K.), MH081884 (N.H.K. and J.R.), MH084051 (R.J.D and N.H.K.), and the HealthEmotions Research Institute. The SOLAR statistical genetics computer package is supported by NIH grant MH059490 (J.B.). The supercomputing facilities used for this work were supported in part by a gift from the AT&T Foundation. We thank the staff at the Wisconsin National Primate Center, the Harlow Center for Biological Psychology, the HealthEmotions Research Institute, the Waisman Laboratory for Brain Imaging and Behavior, Brad Christian, Pat Roseboom, Helen van Valkenberg, Kyle Myer, Liz Larsen, Irina Monosov and Reuven Stone. We also thank Roy Garcia (SFBR) for assistance in genotyping the 5HTTLPR polymorphism.

References

1. Schwartz CE, et al. Inhibited and uninhibited infants "grown up": adult amygdalar response to novelty. Science. 2003; 300:1952–1953. [PubMed: 12817151]

2. Fox AS, et al. Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS ONE. 2008; 3:e2570. [PubMed: 18596957]

3. Kagan J, Reznick JS, Snidman N. Biological bases of childhood shyness. Science. 1988; 240:167–171. [PubMed: 3353713]

4. Fox NA, et al. Behavioral inhibition: linking biology and behavior within a developmental framework. Annu Rev Psychol. 2005; 56:235–262. [PubMed: 15709935]

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

5. Biederman J, et al. Further evidence of association between behavioral inhibition and social anxiety in children. Am J Psychiatry. 2001; 158:1673–1679. [PubMed: 11579001]

6. Kessler RC, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62:617–627. [PubMed: 15939839]

7. Kalin NH, Shelton SE. Nonhuman primate models to study anxiety, emotion regulation, and psychopathology. Ann N Y Acad Sci. 2003; 1008:189–200. [PubMed: 14998885]

8. Kalin NH, Shelton SE. Defensive behaviors in infant rhesus monkeys: environmental cues and neurochemical regulation. Science. 1989; 243:1718–1721. [PubMed: 2564702]

9. Kalin NH, Shelton SE, Davidson RJ. The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. J Neurosci. 2004; 24:5506–5515. [PubMed: 15201323]

10. Gray, JA.; McNaughton, N. The Neuropsychology of Anxiety. 2nd ed.. New York: Oxford University Press; 2000.

11. LeDoux, Joseph E. Emotion Circuits in the Brain. Annual Review of Neuroscience. 2000; 23:155–184.

12. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Molecular Psychiatry. 2001; 6:13–34. [PubMed: 11244481]

13. Fudge JL, Breitbart MA, McClain C. Amygdaloid inputs define a caudal component of the ventral striatum in primates. J Comp Neurol. 2004; 476:330–347. [PubMed: 15282709]

14. Price JL, Drevets WC. Neurocircuitry of Mood Disorders. Neuropsychopharmacology. 2009

15. Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol. 2004; 14:198–202. [PubMed: 15082325]

16. McHugh SB, Deacon RM, Rawlins JN, Bannerman DM. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behavioral Neuroscience. 2004; 118:63–78. [PubMed: 14979783]

17. Chudasama Y, Izquierdo A, Murray EA. Distinct contributions of the amygdala and hippocampus to fear expression. Eur J Neurosci. 2009; 30:2327–2337. [PubMed: 20092575]

18. Machado CJ, Bachevalier J. Behavioral and hormonal reactivity to threat: effects of selective amygdala, hippocampal or orbital frontal lesions in monkeys. Psychoneuroendocrinology. 2008; 33:926–941. [PubMed: 18650022]

19. O'Rourke H, Fudge JL. Distribution of serotonin transporter labeled fibers in amygdaloid subregions: implications for mood disorders. Biol Psychiatry. 2006; 60:479–490. [PubMed: 16414028]

20. Rogers J, et al. Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes Brain Behav. 2008; 7:463–469. [PubMed: 18045243]

21. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001; 158:1568–1578. [PubMed: 11578982]

22. Lyons DM, et al. Early life stress and inherited variation in monkey hippocampal volumes. Arch Gen Psychiatry. 2001; 58:1145–1151. [PubMed: 11735843]

23. Davis OS, Haworth CM, Plomin R. Dramatic increase in heritability of cognitive development from early to middle childhood: an 8-year longitudinal study of 8,700 pairs of twins. Psychol Sci. 2009; 20:1301–1308. [PubMed: 19732386]

24. Visscher PM, Hill WG, Wray NR. Heritability in the genomics era--concepts and misconceptions. Nat Rev Genet. 2008; 9:255–266. [PubMed: 18319743]

25. Hariri AR, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002; 297:400–403. [PubMed: 12130784]

26. Zubieta JK, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003; 299:1240–1243. [PubMed: 12595695]

27. Zhou Z, et al. Genetic variation in human NPY expression affects stress response and emotion. Nature. 2008; 452:997–1001. [PubMed: 18385673]

28. Meyer-Lindenberg A, et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci U S A. 2006; 103:6269–6274. [PubMed: 16569698]

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

29. Kalin NH, et al. The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol Psychiatry. 2008; 13:1021–1027. [PubMed: 18414408]

30. Viviani R, et al. Baseline brain perfusion and the serotonin transporter promoter polymorphism. Biol Psychiatry. 67:317–322. [PubMed: 19878929]

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 1. Glucose metabolism in the anterior temporal lobes is predictive of ATa, amygdala and e, hippocampus (significance of correlations - yellow: p < 0.05, light

orange: p < 0.01, dark orange: p < 0.001, corrected). Pink areas represent 95% spatial

confidence intervals of the peak correlations. b and f, corresponding slices adapted from The

Rhesus Monkey Brain in Stereotaxic Coordinates (2009). c, g, 5-HTT binding differentiates

the CeA region from the anterior hippocampus. d, The CeA, defined by the 5-HTT map,

encompasses the amygdala peak. h, The hippocampal peak is distinct and does not overlap

with the 5-HTT map.

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 2. Peak correlations between AT and anterior temporal lobe glucose metabolisma, Voxel within the amygdala (see Fig 1a) reflecting the peak correlation between

metabolism and AT (r=0.44, p=2.38e-13) and b, voxel within the hippocampus (see Fig 1e)

reflecting the peak correlation between metabolism and AT (r=0.45, p=8.3e-13). 18F-

deoxyglucose values were extracted from each animal, residualized for the effects of age,

sex and gray matter probability, and plotted against individual differences in AT.

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Figure 3. Overlap between regional metabolic activity predictive of AT with regions that are significantly heritablea and b, No significantly heritable voxels were observed in the dorsal amygdala region,

although within the same slice significant heritability was detected in the superior temporal

sulcus. c, Glucose metabolism was significantly heritable in both the right hippocampus and

left hippocampus, d, where it overlaps with the left anterior hippocampal region that

correlated with AT. (yellow = regions predictive of AT from Fig 1; dark green to light

green: FDR: q < 0.05, q < 0.01, q < 0.001).

Oler et al.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Oler et al.

Tab

le 1

Reg

ions

whe

re r

egre

ssio

n an

alys

es r

evea

led

that

AT

was

sig

nifi

cant

ly c

orre

late

d w

ith

brai

n m

etab

olis

m d

urin

g th

e N

o-E

ye-C

onta

ct

chal

leng

e

Dat

a ar

e pr

esen

ted

with

the

dire

ctio

n of

the

corr

elat

ion,

hem

isph

ere,

bra

in r

egio

ns in

volv

ed, a

nd th

e vo

lum

e of

eac

h A

T-c

orre

late

d cl

uste

r. T

he lo

cal

max

ima

for

each

ana

tom

ical

reg

ion

with

in th

e st

atis

tical

clu

ster

with

its

corr

espo

ndin

g t-

valu

e (p

=0.

05, c

orre

cted

) an

d lo

catio

n (i

n m

illim

eter

s re

lativ

e to

the

ante

rior

com

mis

sure

) ar

e al

so r

epor

ted.

CeA

; am

ygda

la c

entr

al n

ucle

us, A

STZ

; am

ygda

lost

riat

al tr

ansi

tion

zon

e.

Clu

ster

s co

rrel

ated

wit

h A

nxio

us T

empe

rmen

tL

ocal

max

ima

wit

hin

clus

ters

Loc

atio

n re

lati

ve t

o an

teri

orco

mm

isur

e (i

n m

m)

dire

ctio

n of

corr

elat

ion

Hem

isph

ere

Reg

ions

wit

hin

clus

ter

clus

ter

volu

me

in m

m3 )

Are

aM

axt-

valu

ex

yz

posi

tive

Ram

ygda

la/te

mpo

ral c

orte

x/85

0.8

dors

al a

myg

dala

(C

eA/A

STZ

reg

ion)

7.68

12.5

00−

0.62

5−

8.75

0

ante

rior

hip

poca

mpu

sve

ntra

l put

amen

7.40

14.3

75−

5.62

5−

8.12

5

supe

rior

tem

pora

l sul

cus

(ant

erio

r)7.

1718

.750

−0.

625

−11

.250

tem

poro

pola

r co

rtex

6.68

19.3

755.

000

−8.

125

Lam

ygda

la/te

mpo

ral c

orte

x/67

5.1

ante

rior

hip

poca

mpu

s7.

61−

12.5

00−

3.75

0−

9.37

5

ante

rior

hip

poca

mpu

sve

ntra

l put

amen

/pos

teri

or a

myg

dala

7.38

−11

.250

−2.

500

−8.

125

mid

hip

poca

mpu

s6.

71−

15.6

25−

7.50

0−

10.6

25

clau

stru

m6.

33−

14.3

753.

125

−10

.000

supe

rior

tem

pora

l sul

cus

6.08

−18

.750

0.62

5−

8.12

5

hypo

thal

amus

5.75

−1.

875

−4.

375

−6.

875

Rpo

ster

ior

thal

amus

11.5

pulv

inar

5.75

10.6

25−

15.6

251.

250

nega

tive

cros

ses

pari

etal

cor

tex

493.

6in

trap

arie

tal s

ulcu

s (r

ight

)−

6.85

4.37

5−

27.5

0016

.875

mid

line

prec

uneu

s (l

eft)

−6.

69−

3.12

5−

29.3

7515

.000

V3

(rig

ht)

−5.

686.

250

−33

.750

9.37

5

Lvi

sual

cor

tex

455.

8V

2−

6.71

−10

.000

−28

.125

−3.

750

pari

etoo

ccip

ital s

ulcu

s−

5.96

−3.

750

−36

.875

1.87

5

V1

−5.

57−

13.7

50−

31.2

50−

1.87

5

Rvi

sual

cor

tex

287.

1V

2−

7.35

6.87

5−

30.6

25−

2.50

0


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Oler et al.

Clu

ster

s co

rrel

ated

wit

h A

nxio

us T

empe

rmen

tL

ocal

max

ima

wit

hin

clus

ters

Loc

atio

n re

lati

ve t

o an

teri

orco

mm

isur

e (i

n m

m)

dire

ctio

n of

corr

elat

ion

Hem

isph

ere

Reg

ions

wit

hin

clus

ter

clus

ter

volu

me

in m

m3 )

Are

aM

axt-

valu

ex

yz

V3

−5.

5611

.250

−31

.875

−6.

875

Rpr

imar

y vi

sual

cor

tex

45.9

V1

−5.

983.

125

−43

.750

−3.

750

Rte

mpo

ral p

arie

tooc

cipi

tal a

rea

8.3

supe

rior

tem

pora

l sul

cus

(pos

teri

or)

−5.

7815

.625

−25

.000

8.75

0


Jonathan A. Oler HHS Public Access Andrew S. Fox Steven E ...

Documents

Transcript of Jonathan A. Oler HHS Public Access Andrew S. Fox Steven E ...